IMMUNE POTENTIAL OF ANIMAL LACKING CLASS IA MOLECULES

描述（由申请方提供）：本提案研究了CD 8 T细胞在抗感染因子免疫应答中的独特功能。我们的主要重点是CD 8 T细胞在单核细胞增生李斯特菌（LM）感染期间的先天免疫反应中发挥的作用。我们最近证实抗原非特异性CD 8 T记忆细胞通过分泌干扰素-γ参与细胞因子驱动的抗LM先天性应答。进一步将“先天性”CD 8 T细胞转移到干扰素-γ缺陷小鼠中可保护它们免受LM感染。我们认为，CD 8 T细胞在INF-γ介导的先天性反应中起着重要作用。在第一个目标中，我们研究了CD 8与NK细胞在提供这种类型的先天保护方面的相对效力。我们假设，效应CD 8 T记忆细胞（TEM）已被证明在适应性免疫反应中发挥次要作用发挥重要作用的先天性反应，并将测试这一假设。在第二个目标中，我们将检查CD 8中央记忆细胞（TCM），TEM和NK细胞在脾脏和肝脏LM感染部位的定位。我们将使用缺乏CCR 7结合趋化因子（CCL-19和-21）的小鼠来评估这种趋化因子-受体相互作用如何影响先天性应答中的CD 8 T细胞。我们还将利用表达Thy-1.1的新BAC转基因小鼠作为IFN-γ分泌的报告基因，原位检查IFN-γ分泌的CD 8和NK细胞。在第三个目标中，我们将确定CD 8 T细胞在将初始CD 4 T细胞极化为Th 1亚群中的作用。在第四个目标中，我们将通过微阵列分析检查由IL-12/18（先天性）激活的CD 8 T细胞与通过TcR（适应性）激活的CD 8 T细胞的基因展示。总之，该提案将增加关于CD 8 T细胞如何在针对细胞内病原体的先天免疫应答中发挥作用的重要新信息。

DESCRIPTION (provided by applicant): This proposal investigates a unique function for CD8 T cells in the immune response against infectious agents. Our major focus is on the role that CD8 T cells play in the innate immune response during infection with Listeria monocytogenes (LM). We recently demonstrated that antigen non specific CD8 T memory cells participate in a cytokine driven innate response against LM by secreting interferon-gamma. Further transfer of "innate" CD8 T cells into interferon-gamma deficient mice protects them from infection with LM. We propose that CD8 T cells play a major role in the INF-gamma mediated innate response. In the first Aim we investigate the relative potency of CD8 vs NK cells in providing this type of innate protection. We postulate that effector CD8 T memory cells (TEM) which have been shown to play a minor role in the adaptive immune response play an important role in the innate response and will test this hypothesis. In the second Aim we will examine the localization of CD8 central memory cells (TCM), TEM, and NK cells at sites of LM infection in spleen and liver. We will use mice deficient in CCR7 binding chemokines (CCL-19 and -21) to assess how this chemokine-receptor interaction affects CD8 T cells in the innate response. We will also utilize new BAC transgenic mice that express Thy-1.1 as a reporter for IFN-gamma secretion to examine IFN-gamma secreting CD8 and NK cells in situ. In the third Aim we will determine the role of CD8 T cells in polarizing naive CD4 T cells to the Th1 subset. In the fourth Aim we will examine by microarray analysis the gene display of CD8 T cells that are activated by IL-12/18 (innate) vs those that are activated through the TcR (adaptive). In summary, this proposal will add important new information on how CD8 T cells function in the innate immune response against intracellular pathogens.